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Targeting Cancer miRNAs by Adoptive Transfer of Programmed B Lymphocytes

通过程序化 B 淋巴细胞的过继转移靶向癌症 miRNA

基本信息

批准号：
8893915
负责人：
MAURIZIO ZANETTI
金额：
$ 16.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8893915
关键词：
Adoptive Transfer B-Cell Lymphomas B-Lymphocytes Biological Models Breast Cancer Cell Breast cancer metastasis CMV promoter Cancer Cell Growth Cells Development Down-Regulation Engineering Future Gene Targeting Genomics Goals Growth Health Hematologic Neoplasms Hybrids In Vitro Injection of therapeutic agent Laboratories Laboratory Finding Leukemic Cell Link Lung Lymphocyte Malignant Neoplasms Manuscripts Measurement Metastatic breast cancer Methods MicroRNAs Modality Mus NOD/SCID mouse Nature Neoplasm Metastasis Normal Cell Oncogenes Oncogenic Pilot Projects Plasmid Cloning Vector Plasmids Regulation Replacement Therapy Solid Neoplasm Solutions Spleen Testing Therapeutic Transgenic Organisms Untranslated RNA Validation Vertebral column Work base cancer cell cancer therapy congenic design high risk in vivo innovation migration neoplastic cell novel strategies outcome forecast overexpression programs research study restoration success tumor tumor progression tumorigenic uptake

项目摘要

DESCRIPTION (provided by applicant): This laboratory recently discovered that primary B-lymphocytes can be programmed for the synthesis and delivery of short, non-coding RNAs in vitro and in vivo. In this revised R21 application we intend to rapidly adapt this new concept and test it in the context of tumor therapy to limit or control cancer cell growth and metastasis. miRNA "signatures" have been identified in both hematological malignancies and solid tumors, distinguishing tumor cells from normal cells. In some instances miRNAs are associated with the prognosis and the progression of cancer. This can happen because of one of two conditions: loss of suppressor miRNAs or overexpression of oncogenic miRNAs. miRNA-based therapy can then be geared at either restore the loss of a particular miRNA or suppress an oncogenic miRNA, respectively. The present proposal aims at gathering first line proof-of-concept that primary B lymphocytes synthesizing and secreting short, non-coding miRNAs can be used to treat cancer in vivo, a new form of therapy that we have termed immunogenomic therapy to typify its hybrid (genomic and immunological) nature. The following three Aims are proposed: (1) Engineer and characterize therapeutic plasmid vectors for miRNA replacement or inhibition; (2) miRNA inhibition: Targeting miR-155 in B leukemic cells; and (3) miRNA replacement: Restoring miR-335 in metastatic breast cancer cells. It is hoped that the work proposed in this high risk/high pay off revised proposal will provide us with the answers needed for a proof-of-principle validation of the new idea. We anticipate that success in obtaining proof-of-concept validation for immunogenomic therapy will open new horizons for the treatment of cancer and metastases.

描述（由申请人提供）：该实验室最近发现，原代B淋巴细胞可被编程用于体外和体内合成和递送短的非编码RNA。在这个修订的R21申请中，我们打算快速适应这个新概念，并在肿瘤治疗的背景下测试它，以限制或控制癌细胞的生长和转移。已经在血液恶性肿瘤和实体瘤中鉴定了miRNA“特征”，从而将肿瘤细胞与正常细胞区分开。在某些情况下，miRNA与癌症的预后和进展相关。这种情况可能是由于以下两种情况之一而发生的：抑制性miRNA的丢失或致癌miRNA的过表达。基于miRNA的治疗可以分别用于恢复特定miRNA的丢失或抑制致癌miRNA。本发明的目的是收集一线概念验证，即合成和分泌短的非编码miRNA的原代B淋巴细胞可用于体内治疗癌症，这是一种新的治疗形式，我们称之为免疫基因组治疗以代表其杂交（基因组和免疫学）性质。提出了以下三个目的：（1）工程化和表征用于miRNA替代或抑制的治疗性质粒载体;（2）miRNA抑制：靶向B白血病细胞中的miR-155;和（3）miRNA替代：恢复转移性乳腺癌细胞中的miR-335。希望在这个高风险/高回报的修订提案中提出的工作将为我们提供新想法的原则验证所需的答案。我们预计，成功获得免疫基因组治疗的概念验证将为癌症和转移瘤的治疗开辟新的视野。